CHAPTER XIV
Lymphocytic Choriomeningitis
Aaron F. Rasmussen, Jr., M.D., and Joseph E. Smadel, M.D.
In World War II, lymphocytic choriomeningitis was a relatively uncommon disease and there were only 33 proved cases of infection with the virus of this disease. During the years 1943 to 1945, inclusive, a total of 758 admissions for this disease were reported on the basis of clinical evidence. However, in a series of 276 cases studied carefully at the Army Medical Department Research and Graduate School, Army Medical Center, Washington, D.C., infection with the virus of lymphocytic choriomeningitis was proved in only 31 instances. Thus, in this study, the virus of this disease was of etiological significance in only about 10 percent of the cases which had been given a final clinical diagnosis of lymphocytic choriomeningitis.
RECENT DESCRIPTION
Major developments in the knowledge of lymphocytic choriomeningitis are all of comparatively recent origin. The years immediately preceding and following World War II witnessed fundamental changes in the popular conception of this disease. In 1925, Wallgren1 first attempted to differentiate benign, nonbacterial lymphocytic meningitis from the acute bacterial and mycotic meningitides as well as from those viral infections characterized by primary damage to nervous tissue rather than to the meninges. In 1933 Armstrong2 discovered the virus of lymphocytic choriomeningitis, and in 1934 Rivers and Scott3 found this virus to be the cause of human infections with the typical picture of Wallgren's aseptic meningitis. The virus was found to be widely distributed in mice and other animals, and most human infections were related to contact either with wild mice or with mice or other animals in the laboratory.4
The conception of this disease as a clinico-etiological entity was rather generally accepted for the next 5 years. By 1942, it was apparent that
1Wallgren, A.: Une nouvelle maladie infectieuse du systeme nerveux central? Acta paediat. 4: 158-182, 1925.
2Armstrong, C., and Lillie, R. D. : Experimental Lymphocytic Choriomeningitis of Monkeys and Mice Produced by a Virus Encountered in Studies of the 1933 St. Louis Encephalitis Epidemic. Pub. Health Rep. 49 : 1019-1027, 31 Aug. 1934.
3Rivers, T. M., and Scott, T. F. M.: Meningitis in Man Caused by a Filterable Virus. Science 81 : 439-440, 3 May 1935.
4Armstrong, C.: Studies on Choriomeningitis and Poliomyelitis. Bull. New York Acad. Med. 17: 295-318, April 1941.
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lymphocytic choriomeningitis virus was not the etiological agent in all cases of aseptic meningitis, and, further, that infections with this virus in man could assume a variety of forms.5 These facts were not generally realized, however, and as late as June 1942 acute aseptic meningitis was listed as a synonym for lymphocytic choriomeningitis in Standard Nomenclature of Disease and Standard Nomenclature of Operations,6 published by the American Medical Association. The Office of the Surgeon General followed this nomenclature and, from 1943 to 1945, listed choriomeningitis, lymphocytic, acute or chronic, as a specific infection. At the same time, it was realized that accurate differential diagnosis on a clinical basis was not possible, and the Office of the Surgeon General issued a circular letter7 which urged that materials from all cases of suspected viral infection of the central nervous system be submitted to the Virus Laboratory at the Army Medical School, Army Medical Center, Washington, D.C., or later to the appropriate medical general laboratory, for special studies.
Thus, for the first time, all the available procedures for the diagnosis of viral infections of the central nervous system were applied to a large number of cases occurring in a variety of geographic locations all over the world. Most of these procedures had previously been employed, in limited studies on selected materials, only in the laboratories in which they had been developed. The results of the Army's experience were of great interest because they indicated the relative infrequency with which the virus of lymphocytic choriomeningitis caused the clinical syndrome with which it had originally been associated.
INCIDENCE
Cases determined by laboratory diagnosis.-The two methods employed for the laboratory diagnosis of lymphocytic choriomeningitis were (1) isolation and identification of the virus and (2) demonstration of the appearance, or rising titer, of the specific complement-fixing or neutralizing antibodies of lymphocytic choriomeningitis.
During the entire war period, specimens were studied at the ArmyMedical School, ArmyMedical Center, from over 500 patients with clinical findings suggesting this disease, and sufficient materials for adequate investigative studies were obtained from 276 of these. Thirty-one cases of lymphocytic choriomeningitis were found among the 276. Each of these was diagnosed on the basis of positive results obtained by one or more of the diagnostic methods. Thirty of these were from the United States, and one
5Smadel, J. E., Green, R. H., Paltauf, R. M., and Gonzales, T. A.: Lymphocytic Choriomeningitis : Two Human Fatalities Following an Unusual Febrile Illness. Proc. Soc. Exper. Biol. & Med. 49 : 683-686, April 1942.
6The fourth edition of this work, published in January 1952, contains the same listing.
7Circular Letter No. 74, Office of the Surgeon General, U.S. Army, 19 Mar. 1943, subject : Neurotropic Virus Diseases.
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was from the Pacific. Two additional cases from the European theater were diagnosed in the 1st Medical General Laboratory.
Occasionally, infections with lymphocytic choriomeningitis virus are of a severe nature. Two fatal cases, proved by the recovery of the virus from tissues of the central nervous system, occurred in the Army. Both patients (Armed Forces Institute of Pathology Accession Nos. 82,126 and 82,722) showed symptoms of encephalitis and were found at autopsy to have an extensive, diffuse, nonsuppurative encephalomyelitis.
Cases diagnosed clinically.-Clinical criteria for diagnosis of this disease were essentially those outlined for aseptic meningitis. These criteria include the following: An acute onset, headache, stiff neck, and other signs and symptoms of meningeal irritation; a lymphocytic pleocytosis; and the exclusion of pathogenic bacteria and higher organisms by bacteriological examination of the spinal fluid.
During the years 1943 to 1945, in which lymphocytic choriomeningitis was accepted as a final clinical diagnosis, 758 admissions for this disease were reported in the Army (table 37).
TABLE 37.-Admissions for lymphocytic choriomeningitis in the U.S. Army by theater orarea and year, 1943-45
Theater or area | 1943 | 1944 | 1945 |
Continental United States | 95 | 98 | 140 |
Overseas: | |||
| Mediterranean1 | 63 | 44 | 60 |
| Europe | --- | 10 | 115 |
| Pacific | 5 | 14 | 40 |
| Other areas2 | 14 | 15 | 45 |
| Total | 177 | 181 | 400 |
1Includes North Africa.
2Includes the Middle East, China-Burma-India Theater,North America (Alaska and Iceland), and Latin America.
On the basis of the careful studies in the laboratory in which 31 of 276 cases were proved to be caused by lymphocytic choriomeningitis, it is probable that 1 in 10 of the total number of 758 admissions was actually caused by the virus of this disease. The overall incidence for the war years can be estimated at about 76 cases plus the few cases occurring in 1942 before the disease was reportable on clinical grounds.
ETIOLOGY OF ASEPTIC MENINGITIS NOT CAUSED BY THEVIRUS OF LYMPHOCYTIC CHORIOMENINGITIS
The etiology in the remaining cases is a subject of great interest. Serums from this group of patients were tested for the complement-fixing
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antibodies of mumps,8 and about 1 in 8 cases was shown to have been caused by that virus, even though other signs of mumps infection were absent. This still leaves three-fourths of the total group undiagnosed. It is reasonable to assume that abortive infections with a number of other neurotropic viruses might result in a febrile illness and a meningeal reaction. Selected serums from patients in this aseptic meningitis group were tested for the antibodies of St. Louis encephalitis, western equine encephalitis, eastern equine encephalitis, Japanese or type B encephalitis, Russian encephalitis, West Nile encephalitis, and Hawaiian dengue and also for the antibodies of the psittacosis-lymphogranuloma venereum group. In no instance were significant data obtained. Some of these cases probably were abortive poliomyelitis for which no practical test is available.
Postwar developments have shown that the virus of encephalomyocarditis caused an isolated outbreak of disease with similar features in the Philippines,9 and it is known that the Coxsackie or "C" virus10 can cause a significant number of such cases. Leptospirosis may also present a similar picture.
8Rasmussen, A. F., Jr. : The Laboratory Diagnosis of Lymphocytic Choriomeningitis and Mumps. Rocky Mountain Conference on Infantile Paralysis, Denver, Colo., 1946, pp. 45-60.
9Smadel, J. E., and Warren, J. : The Virus of Encephalomyocarditis and Its Apparent Causation of Disease in Man. J. Clin. Investigation 26: 1197, November 1947.
10Curnen, E. C. : Human Disease Associated With the Coxsackie Viruses. Bull. New York Acad. Med. 26 : 335-342, May 1950.
